21-bromo steroid adducts



Patented Dec. 9, 1952 UNITED STATES PATENT. OFFICE iZI-BROMO STEROID ADDUCTS Robert H. Levin, A Vern McIntosh, Jr., and George B. Spero, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a

corporation of Michigan No Drawing. Application September 12, 1950, Serial No. 184,513

4 Claims.

t .OQ I

wherein Ac is the residue of an-organic carboxylic acid, especially those containing from one to eight carbon atoms, inclusive; and A is the adduct radical of a dienophile selected from the group consisting of maleic acid, maleic anhydride, and maleic acid diesters containing from one to eight carbon atoms, inclusive, in the esterifying group.

It is an object of the present invention to provide a novel group of compounds'which are useful in the preparation of steroid compounds containing an oxygen atom at carbon atom eleven. Another object of the invention is the provision of a process for the production, of the novel compounds, adducts of 21-bromo-3- acyloxy- 5,7,9(ll) -pregnatrien-'20-ones. Other objects 'of the invention will become apparent hereinafter.

The compounds of the present invention, as

previously stated, are useful in thepreparation of steroid compounds having an oxygen atom attached to carbon atom eleven. Such compounds are of particular interest in the field of steroid research due to the biological activity of the cortical hormones and certain known derivatives thereof, which oxygenated steroids are known to have biological effects differing markedly from the unoxygenated steroids. It is, therefore, of importance to investigate the oxygenated derivatives of such adducts, particularly those oxygenated at carbon atom eleven, as well as to investigate the biological activity of the adducts themselves and their transformation products. is moreover emphasized by the acute'shortage of adrenal cortical hormones, and the absence of any present suggestion for alleviation of the said shortage except through organic synthesis.

Novel compounds of the present invention The importance of such investigation which are of particular interest are those compounds of the above generic formula wherein AcO represents an ester of the 3-hydroxy group with acarboxylic acidcontaining up to and including eight carbon atoms. Among theacids which can be used are formic, acetic propionic, butyric, valeric, hexanoic, heptanoic, octanoic, succinic, glutaric, cyclopentanoic, cyclohexanoic, benzoic, toluic, and the like. Preferred acids are the lower-aliphaticacids. The acids may also contain substituents, such as halo, alkyl, and methoxy, which are non-reactiveunder'the-reaction conditions employed. The adduct bridge (-A-) in such compounds may be. represented by the graphic formula:

COOR

wherein R represents hydrogen or the organic residue of an alcohol. Such esters include the methyl, ethyl, propyl, .isopropyl, butyl, isobutyl, lauryl, heptyl, octyl, cyclopentyl, cyclohexyl, benzyl, and the like esters. The esterifying radical may also contain non-reactive substituents, such as halo, methoxy, or hydroxy, if desired. While the esters of the maleic acid adduct are described herein with particular reference'to the methyl esters, the preferred embodiment of R is a lower-alkyl radicalcontainingfrom one to eight carbon atoms, inclusive. Alternatively, the adduct may be depicted by the graphic formula:

which is representative of the maleic anhydride adduct.

The compounds of the invention are usually colorless crystalline solids. The acid or anhydride adducts are readily converted into diester adducts by esterification with conventional reagents such as the diazoalkanes [Wilds et al.,

3 J. Org. Chem. 13, 763 (1948) l. The dibasic acids may be converted into their corresponding anhydrides by heat.

The compounds of the present invention have the formula: 5

(llHzBl c=0 on; 1

A00 V wherein A and Ac have the values previously assigned. These 2l-bromo compounds are prepared by the selective bromination of the corre- 2O sponding 3-acyloxy-5,'7,9 l1) -pregnatrien--one adduct using about one mole of bromine, preferably a slight excess over one mole of bromine, per mole of starting steroid. The steroid is dissolved inan organic solvent such as a halogenated hydrocarbon, e. g., chloroform, or an ether, 0 e. g., diethyl ether or dioxane, and a solution of bromine in the same organic solvent added portionwise thereto at a temperature between about zero and thirty degrees centigrade. The reaction proceeds rapidly after an initial induction period, and is apparently catalyzed by the first hydrogen bromide formed. After the bromine is taken up by the steroid, as indicated by loss of color in the solution, the solution may be evaporated to dryness and the desired compound crystallized from D an organic solvent to give a more highly purified product.

The 3 acyloxy 5,7,9(11) pregnatrien-ZO-one adducts are conveniently prepared by the selective oxidation of an enol ester of an adduct of 3-acyloXybisnor-5,7,9(ll) -cholatrien-22-al, represented by the formula:

wherein A and Ac have the values previously given, to the action of an acid anhydride or an 75 acid halide in the presence of an alkaline salt of the acid. The starting adducts of 3-acyloxybisnor-5,7,9(11) -cholatrien-22-als can be prepared from adducts of 3-esters of dehydroergosterol by selective oxidation as described and claimed in the copending application Serial 111,100 of Robert H. Levin, filed August 18, 1949, and as more fully described hereinafter.

The 3-esters of dehydroerg'osterol, from which the 3 acyloxybisnor 5,7,9(ll) cholatrien-22-al adducts are prepared, can be synthesized in several ways starting with ergosterol. For example, ergosterol can be transformed to dehydroergosterol with mercuric acetate according to known methods [Windaus et al., Ann. 465, 157 (1928)] and the 3-hydroxy group of the dehydroergosterol acylated by known procedure. Alternatively the 3-hydroxy group of ergosterol can be acylated prior to the preparation of the dehydro derivative, a procedure which is particularly preferred in the preparation of the 3-acetoxy derivative. The adducts of dehydroergosterol are then prepared by the addition of maleic anhydride or the like to dehydroergosterol or a 3-ester thereof according to known methods [Honigmann, Ann. 508, 89 (1934)]. The anhydrides can then be converted to their corresponding acids and esters if desired.

The ester group, when present in the 3-position of dehydroergosterol, is for the purpose of protecting the B-hydroxy group in subsequent chemical reactions. For this purpose any convenient ester of an organic carboxylic acid, which is nonreactive under the conditions of the reaction, is suitable. The preferred acids are the fatty acids such as formic, acetic, propionic, butyric, valeric, hexanoic, heptanoic, octanoic; dibasic acids such as malonic, succinic, phthalic; cycloaliphatic acids such as cyclopentanoic and cyclohexanoic; and aromatic acids such as benzoic, toluic, naphthoic, and the like. The acids may also contain substituents such as halogen, alkyl, the methoxy radical, and the like, and these substituents will be carried throughout the synthesis. If desired, the acyl group can be changed to another acyl group by saponifying the ester to give a 3-hydroxy compound, which can then be re-esterified as previously described.

A preferred method for preparing some of the dehydroergosteryl adducts comprises the saponification of a 3-acyloxy adduct of dehydroergosterol with dilute alkali followed by acidification. The 3-hydroxy dicarboxylic acid thus formed can be converted to the 3-hydroxy anhydride by heat, or it can be converted to any desired 3-acyloxy anhydride adduct by heating under reflux with the appropriate acid anhydride or chloride in pyridine solution. Dialkyl esters of the previously mentioned dicarboxylic acid adducts can be prepared by subjecting the acid to the action of an esterification reagent such as a diazoalkane [Wilds et al., J. Org. Chem. 13, 763 (1948) l, e. g., diazomethane, diazoethane, diazobutane, and the like.

The selective oxidation of an adduct of dehydroergosterol, or a 3-ester thereof, to produce an adduct of 3-hydroxybisnor-5,7,9(11) -cholatrien- 22-al, or a 3-ester thereof, is accomplished by dissolving the dehydroergosteryl adduct in a suitable solvent, cooling to about minus 80 to plus 30 degrees centigrade, and passing ozone into the solution until about 1.0 to 1.25 moles of ozone per mole of adduct have been absorbed. The tem perature of the solution should be maintained below plus 30 degrees centigrade, preferably between a temperature of minus 30 and minus degrees centigrade, during the additionrof :ozone. although temperatures as low as minus '80 -and as high as plus 30 degrees centigrade are operative. The lowertemperatures of thepreferred range are readily obtained by cooling'the'solution of the adduct with a bath of solid carbondioxide in acetone or the like, although various other methods of coolingcan be used. Many of themolecularoxygen is prevented fromoxidizing-the aldehyde thus formed. This can be conveniently accomplished by decomposing the ozonide in: glacial acetic acid by the addition of finely'powdered zinc.

As is conventional with ozonizations when' conducted in solvents, other than 'glaciahacetic acid, the-solvent used for ozonization is"rep1aced,;after completion of the ozonization, "by:adding glacial aceticacidand removing the lower-boiling solvent'by fractional distillation. Alternatively; the

solvent can be removed bycareful warming .under redu-cedjpressure prior to the addition-of glacial acetic acid, if desired.

.After decomposition of the ozonideandremoval of the .zinc, the aldehyde can :be recovered by diluting the acetic acid with water, nor in :other conventional manner, such as'by formationiofian aldehyde derivative, 'e. g, the dinitrophenylhydrazone.

Adducts of 3,22-diacyloxybisnor-53,911l'),20- (22) -cholatetraenes [22-enol-esters of adducts of 3-a-cyloxybisnor-5,7,9 l1) -cholatrien-22-alsl can be conveniently prepared by heating the corresponding 3-hydroxy or. 3-.acyloxy aldehyde maleic acid, maleic acid anhydride, or maleic acid ester adduct with a large excess of .an organic -.carboxylic acid anhydride in the presence of a small amount of the alkali metalsaltof .theacid corresponding to the anhydride employed oran acid catalyst such as para-toluene sulfonic or sulfuric acid. The preferred .anhydrideis acetic anhydride, but other anhydrides, such as propionic, butyric, valeric, hexanoic,'.and octanoic anhydrides, as well as'benzoic acid anhydride, orthotoluic acid anhydride, and the like, are also oper ative. The acid anhydrides canals'oibe substituted'by non-reactive groupasuch as halo,.alky1, and methoxy, as in the case of chloroac'etic, ortho-toluic, or methoxybe'nzoic acid anhydrides. The reaction can be conveniently. .followedby observing the color changesinthe-reaction mixture, optimum yields'being obtained 'by discon tinuing the application ofiheat whenthe colorof the solution changes from yellow to brown. Ordinarily the reaction is heated .at about 140 degrees centigrade ,for from about four to six I hours, but temperatures as low as IOOandas high as 180 degrees centigrade are also operative. The reaction is usually conducted at the'boiling point of the anhydride, but in the lease of the higher-boiling anhydrides, such as benzoic anhydride, a suitable temperature control, such as -150degrees centigrade, must be used, since the'adduct otherwise tends to decompose .inithe higher temperature range. If "a. 3-;hydroxyialdehyde Jadductis thus reacted with. an ranhydride, the 'hydroxy group will be acylated, and, similarly, if:a:maleic acid adductisused instea'dtof a "diester-por an .anhydride, the anhydrlde willabe formed. The enol ester .can be isolated by removing the excess anhydride under :reduced pressure, and separating the enol ester .ifrom alkali metal salts,- which'procedure-yields aprodnot sufficiently pure ;for most purposespbut-which can be furtheripurified :by recrystallization :from acetone-water, acetone pentane, or like solvents, if desired.

The ozonization of the thus prepared enol acylate ltoproduce a 3-acyloxy-:5,'Z,9 (.11) -pregnatrien-20-one adduct involves 1 dissolving \the. enol ester; in a---suita'ble solvent, cooling to about minus eighty degrees centigrade to plus "thirty degrees centigrade, and passing ozone, .ozonized-air, or ozonized oxygen intothe solutionuntillabout11 .0

to about 1.25 moles, preferably .1.0 to .-1.1:moles,

of ozone percmole o'f 'addu-ct haveibeenabsorhied. Theeaddition .of ozone to :the 20:22 double bond is;so rapid that .only a small amount .of-ozone escapes from the reaction mixture, and the amount of ozone ordinarily required therefore closely approximates the theoretical amount. Loss to the solvent, ii any loss occurs, must be taken into consideration in calculating :the amount of ozone tobeintroduced; Thetemperature of the solution shouldibec-maintainedcbelow plus thirty degreescentigrade, preferably 'between .a temperature of .minus thirty and imlnus seventy degrees centigrade, during the'addition of ozone, although temperatures as low as minus eighty and as high as plus thirty degrees centigrade are operative. The lowertemperatures of therange are readily obtained 'by cooling the solution'of the adduct-with a bath of solid carbon.

composed under conditions normally employed for;decom position of such compounds. This can conveniently: be accomplishedby dficfimposingthe ozonide with hydrogen peroxide, by hydrolysis; by treatment with zinc.in;;glacial-acetic acid, or byiaicatalytic amount of ;colloidal metal-such-as silver, platinum, or palladium in a solvent, such as glacial-acetic acid, alcohol, or ethyl acetate, in which latter case reductive conditions, .e g.,,a hydrogen atmosphere, are .alsoemployedi The use of reductive conditions is *well established in the art; [Hill and Kelly, Organic Chemistry]? page-53,,The Blackiston Company, Philadelphia (1934); Church et 'al, J. Am. Chem. .Soc. 56, 176-184 (1934); Gilman Organic Chemistry, second edition, page 636, John Wiley and Sons, New York (1943); Long, Chem. Reviews 27, 452-454 (1940) 1.

,As is conventional with decomposition of ozonideswith zinc, whenthe ozonizations are conducted in solvents other than glacial acetic acid, theisolvent used for theozonizationis replaced, after completion of the ozonization, by adding glacial acetic acid and removing th'elower-boiling solvent by fractional distillation, or the solvent can be removed by careful'warming under re: ducedpressure prior to the addition of acetic acid, if desired. After decompositionor the' 20 :122

ozonide and removal of the metal, the ketone can be recovered by diluting the acetic acid with water, or by other conventional procedure for the recovery of ketones, such as by formation of a carbonyl derivative, e, g., the 2,4-dinitrophenylhydrazone. Recrystallization from acetone or the like results in a more highly purified ketone product.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1.DIMETHYL MALEATF. ADDUCT or Dnnroiiomcosrimrr. BENZOATE To a solution of 21 grams of dimethyl maleate adduct of dehydroergosterol in 69 milliliters of warm pyridine was added 9.5 milliliters of benzoyl chloride. After standing at room temperature for fifteen minutes, the mixture was poured into 1400 milliliters of ice-water and the solid removed by filtration, dried, and recrystallized from acetone. There was thus obtained 26.4 grams of dimethyl maleate adduct of dehydroergosteryl benzoate, melting at 203 to 205.5 degrees centigrade.

PREPARATION 2.DIMETHYL MALEATE ADDUCT or DEHYDROERGOSTERYL ACETATE In a manner essentially that described in Preparation 1, the dimethyl maleate adduct of dehydroergosteryl acetate, melting at 177 to 179 degrees centigrade, was prepared from the dimethyl maleate adduct of dehydroergosterol and acetyl chloride.

PREPARATION 3.-DIMETHYL MALEATE ADDUCT or DEHYDBOERGOSTERYL FORUATE A solution of six grams of dimethyl maleate adduct of dehydroergosterol in fifty milliliters of 87 percent formic acid was heated under reflux for one hour, cooled, and the dimethyl maleate adduct of dehydroergosteryl formate filtered therefrom. Upon crystallization from acetone, the purified material melted at 177.5 to 178.5 degrees centigrade.

I PREPARATION 4.MALE1o ACID America or DEHYDROERGOSTEROL A solution of 2.0 grams of sodium hydroxide in twenty milliliters of water was added to a solution of 1.73 grams of the maleic anhydride adduct of dehydroergosteryl acetate (M. P. 230-232 degrees centigrade) in forty milliliters of dioxane. The mixture solidified, but dissolved on addition of 300 milliliters of water and heating to eighty degrees centigrade After half an hour the solution was cooled and made acid with aqueous three normal hydrochloric acid, to give 1.61 grams of precipitate. On crystallization from a dioxanewater mixture, the maleic acid adduct of dehydroergosterol melted at 190-192 degrees centigrade.

PREPARATION 5. MALlcic ANHYnR-IDE Anouc'r or 3-HEPTANOYLOXYDEHYDROERGOSTEROL heptanoyloxydehydroergosterol, melting at 186- 191.5 degrees centigrade.

PREPARATION 6,-MALEI0 ANHYDBIDE ADDUGT or 3- BETA-ACETOXYBISNOR-5,7,9 (11) -CHOLATRIEN-22-AL A solution of 5.35 grams of the maleic anhydride adduct of 3-beta-acetoxydehydroergosterol in 107 milliliters of methylene chloride was cooled to about minus seventy degrees centigrade and ozonized until 505 milligrams of ozone had been absorbed. The temperature of the solution was then gradually raised to about plus ten to fifteen degrees centigrade, whereupon seventy milliliters of glacial acetic acid was added and the methylene chloride removed under reduced pressure. Seven grams of zinc dust was then added to the cold solution at a uniform rate over a period of ten minutes, while keeping the reaction temperature below plus twenty degrees centigrade. After being stirred for fifteen minutes, the mixture was filtered and the filtrate poured into water. There was thus obtained 4.31 grams of maleic anhydride adduct of S-beta-acetoxybisnor-5,7,9(11)-cholatrien-22-al, a fine white powder which melted at 187497 degrees centigrade.

To a solution of 0.30 gram of the maleic anhydride adduct of 3-beta-acetoxybisnor-5,7,9- (11)-cholatrien-22-al, in thirty milliliters of ethanol, was added twenty milliliters of alcohol containing one percent 2,4-dinitrophenylhydrazine and three percent concentrated hydrochloric acid. The mixture was allowed to stand for one hour at room temperature and then laced in a refrigerator to complete precipitation of the yellow crystals. The precipitate was then collected and recrystallized from a mixture of chloroform and alcohol, to give the 2,4-dinitrophenylhydrazone of the maleic anhydride adduct of 3-beta-acetoxybisnor-5,7,9 (11) -cholatrien-22- al, melting at 269-271 degrees centigrade.

PREPARATION 7.-MALEI0 ANHYDRIDE AoDUo'r or 3- mzrA-Acnroxrmsnonfi,7,9(11)-cI1oLArRIEN-22-Ar,

A two-liter round bottom flask was charged with fifty grams (0.93 mole) of dehydroergosteryl acetate maleic anhydride adduct and one liter of methylene chloride. The solution was cooled to Dry-Ice temperature with a trichloroethylene bath and ozonized oxygen passed through at a rate of 1200 milliliters of oxygen per minute (at this rate the ozonizer was producing about 36 milligrams of ozone per minute). The fiow of ozonized oxygen was maintained for 128 minutes, a total of 4608 milligrams (105 percent) of ozone being passed into the solution. The reaction mixture was transferred to a two-liter, round-bottom flask fitted with a capillary and a condenser for downward distillation, 300 milliliters of acetic acid added, and the methylene chloride distilled over in vacuo at forty degrees centigrade or below. The flask was then placed in a water bath and fitted with a stirrer. An additional 200 milliliters of acetic acid was added and the ozonide decomposed by the addition of fifty grams of zinc dust. The zinc dust was added in portions over a period of twenty to thirty minutes while the solution was stirred and the temperature maintained at seventeen to twenty degrees centigrade. After addition, the mixture was stirred for another twenty minutes and then filtered. The precipitated zinc dust was washed by filtering milliliters of acetic acid therethrough, and the filtrate gradually diluted with water 100 to 1200 milliliters) until the product had been drowned out. The product was then cooled'in the-refrigerator overnight and filtereds. The yield ofcrystalline product was 42 grams, assaying 89-95 percent of the desired aldehyde.

PREPARATION S In a manner essentially that described in Preparation 6, the following compounds wereprepared.

(1) Maleic anhydride adduct of 3-beta-for moxybisnor-5,7,9(1l) -cholatrien-22-al, melting ati95- 30-degrees centigrade. 2,4-dinitrophenylhydrazone, melting at 165-168 degreescentigrade;

(2) maleic anhydride adduct of 3-beta-heptanoyloxbisnor-5,7,9 (11) -cholatrien-22-al, melting at 1975-499 degrees centigrade. 2,4-dinitrophenylhydrazone, melting at 253-257 degrees centigrade.

(3) dimethyl maleate adduct of B-betabenzoyloxybisnor-5,7,9 (1 1) -cholatrien-22-al, melting at 183-187 degrees centigrade. 2,4-dinitrophenylhydrazone, melting at 22 l24=9 degrees centigrade.

(4) Dimethyl maleate adduct of 3-beta-acetoxybisnor-5,7;9 (11) -cholatrien-'22-al, melting at 172-178 degrees centigrade. 2,4-dinitrophenylhydrazone, melting at 238 to 244 degrees centigrade.

(5) Dimethyl maleate adduct of 3 -hyd'roxybisnor-5,7,9'(1l) cholatrien 22 al, melting at 163470 degrees centigrade. 2,4-dinitrophenylhydrazone, melting at250-254 degrees centigrade.

In a manner similar to the above, the maleic anhydride adduct of 3hydroxybisnor-5,7,9(11)- cholatrien-22eal is obtained from dehydroergosteryl maleic anhydride adduct; the maleic acid adduct of 3-hydroxybisnor-5,7,9(11) -cholatrien- 22-al is obtained from dehydroergosteryl maleic acid adduct; and 3-acyloxybisnor-5,7,9(l1) -cholatrien-22-al maleic acid adducts are obtained from they maleic acid adduct of 3-acyloxydehydroergosterol's.

PREPARATION S).DIMETHYL MALEATE' ADDUCT 0F 3-HYDROXYBISNOR-5,7,9(11)CHOLATRIEN-22AL 'A' solution of 2.69 grams (;005" mole) of'the dimethyl ester of. the maleic acid adduct of dehydroergosterol, in eighty milliliters of methylene chloride, cooled by a Dry-Ice, and trichloroethylene. bath, was treated with ozonizedoxygen until utes, wherea-fter thezinc was separated-by filtra tion. The filtrate was diluted with water" to cloudiness, extracted with ether, the ether ex-- tract washed with sodium bicarbonate and then with water to neutrality, the solution then dried over sodium sulfate-andevaporated to dryness in vacuo.- The residue was crystallized from acetic acidand' water, giving 1.92 grams (81.5 percent of thetheoretical) melting point'91-97 degrees centigrad-e, which yielded a dinitrophenylhydrazone derivative in 725 percent yield, melting point 212-238 degrees centigrade. recrystallized and found to have a purified melting point of 163-170-degrees centigrade, while the dinitrophenylhydrazone derivative was re- The aldehyde was milliliters of water.

. 1' 0 crystallized until a melting point or 250-254 degrees centigrade wasattained.

PREPARATION 10.1\1ALEIC ANHYDRIDE ADDUCT or 3- BETA-ACETOXY-22-ACETOXYBISN Ola-5,7,9 11 ,20 (22 CHOLATE'IRAENE A mixture oftwenty grams of themaleic anhydride adduct or 3-beta-acetoxybisnor-5,7,9- (11)-cholatrien-22-a1,. six grams: of. anhydrous sodium acetate, and 600 milliliters of acetic anhydride, washeated under reflux forsix hours, whereafter volatile components. were" removed under reduced pressure. The resulting, solid was.

PREPARATION 11 In a manner essentially that described in Preparationv 10,- the following compounds were prepared:

(1) The dimethyl maleate adduct of. B-betabenzoyloxy 22 acetoxybisnor-5,7,9(l1) ,20 (22),--

cholatetraene, which melted at 210 to 211 degrees centigrade.

(2) The dimethyl maleate adduct of" S-betaacetoxy 22v acetoxybisnor 5,7,9(11)-,20(22)- cholatetraene, which ,meltedat 181 to. 183-degrees centigrade.

In the'same manner asgiven above, 22-acyloxy, e. g., formoxy, acetoxy; propionoxy, butyroxy, valeroxy, hexanoyloxy, heptanoyloxy, octanoylioxy, benzoyloxy, and the like 3-acyloxybisnor- 5,7,9 (11) ,20(22) -cholatetraene adducts, are. obtained from the compounds of Preparations 6, 7,

and 8. Such representative compounds include 3 iormoxy 22-acetoxybisnor-5,7,9(11 ,20(22)--,

cholatetraene, 3 propionoxy-22-acetoxybisnor-- 5,7,9 (11') ,20(22) -cholatetraene, 3,22 --dipropionoxybisnor-5-,7,9(11) ,20(22) -cholatetraene, and; 3- heptanoyloxy 22-octanoyloxybisnor 5,7,9(-11):,,-

20(22) -cholatetraene adducts with maleic anhydride or maleic acid esters such asthedimethyh maleate, diethyl'maleate, dipropylmaleate, diiso propyl maleate, dibut-yl maleate, dioctyl maleate,-,7

dibenzyl maleate; and the like.

PREPARATION 121-MALEI0 ANHYDBIDE ADnUoroE- 3-BETA-A'CETOXY-5,7 ,9 (11) -PREGNATRIEN-20-ONE.

seventy degrees' centigrade and ozonized until i83 milligramss of' ozone had-been absorbed Fifty milliliters of glacial acetic acid was then added andv the methylene chloride removed under-reduced. pressure. Arr-additional thirty millilitersof glacial acetic acid was thenadded and the ozonide decomposed. by: addingseven grams o'f powdered zinc'atr a. substantially uniform rate while: maintaining the-reaction temperature between seventeen and twentydegrees 7 centigra'de.

The mixture was stirred for an additionaltwenty minutes, filtered,v andv the zinc, washed with 140 millilitersfo'f. glacial acetic acidI The-organic extracts werecomhined' and diluted'with seventy When crystallization comtigrade.

263.5 to 264.5 degrees centigrade.

PREPARATION 13.-MALEI ACID ADDUCT 0F 34mm- HYnR0xY-5,7,9 (11) -PREGNATRIEN--0NE A solution of 4.52 grams (0.01 mole) of the maleic anhydride adduct of 3-beta-acetoxy- 5,7,9(11) -pregnatrien-20-one, M. P. 263-2645 degrees centigrade, in a mixture of 100 milliliters of 1,4-dioxane and 400 milliliters of water containing four grams (0.10 mole) of sodium hydroxide was allowed to stand at room temperature for two and one-half hours, whereupon a small quantity of plate-like crystals formed. These were dissolved by heating the mixture to seventy degrees centigrade for one-half hour. The reaction mixture was then made acid with fifty milliliters of three normal hydrochloric acid and refrigerated to give a precipitate of 3.05 grams of needle-like crystals melting at 173-177 degrees centigrade. On crystallization from a dioxane-water mixture, the compound melted at 211-215 degrees centigrade. The melting point was found to vary somewhat with the rate of heating.

PREPARATION 1-LDIMETHYCL MALEATE or 31mm- HYnnoxY-5,T,9 (11) -PREGNATRIEN-20-ONE A suspension of 0.400 gram of the maleic acid adduct of 3-beta-hydroxy-5,7,9(1l)-pregnatrien- 20-one, in fifty milliliters of dry ether, was cooled in an ice-salt bath while a slight excess of diazomethane in methylene chloride was added over a -minute period with stirring. Ten minutes after addition was complete, the solution was placed on a steam bath and concentrated rapidly to dryness. The residue was crystallized from an acetone-water mixture to give 0.34 gram of the dimethyl maleate of B-beta-hydroxy- 5,7,9(11)-pregnatrien-20-one, melting at 193-195 degrees centigrade. After chromatography and recrystallization, the compound melted at 192-197 degrees centigrade.

In the same manner as given above, other dialkyl maleates, e. g., the diethyl, dipropyl, diisopropyl, dibutyl, and dioctyl maleates of 3-hydroxy-5,7,9(11) -pregnatrien-20-one are prepared from 3 hydroxy 5,7,9(11) -pregnatrien-20-one maleic acid adduct and the appropriate diazoalkane, or by other equivalent esterification procedure.

PREPARATION 15.DIMETHYL MALEATE or 34mm- AOETOXY-5,7,9 (11) -PREGNATRIEN-20-ONE Analysis:

Calculated for C29H38o7 C, 69.86; H, 7.68 Found 69.81; 7.86 69.70; 7.62

By the same manner of esterification, the following C-3 esters were prepared: (1) dimethyl maleate adduct of 3-beta-formoxy-5,7,9(11)- pregnatrien-ZO-one, melting point 223-230 degrees centigrade, and the dimethyl maleate adduct of 3-beta-benzoyloxy-5,7,9(11)-pregnatrien-20-one, melting point 250-254 degrees centigrade.

PREPARATION 16.l\[AI.EIC ANHYDRIDE ADDUC'I or 3- BETA-HEPTANOYLOXY-d? ,9 11 -IREGNATRIEN-20-ONE The maleic anhydride adduct of 3-beta-heptanoyloxy-5,7,9(11) -pregnatrien-20-one, melting point -171 degrees Centigrade, was prepared by refluxing the maleic acid adduct of 3-beta-hydroxy-5,7,9(l1) -pregnatrien-20-one with heptylic anhydride and pyridine for a period of twenty hours, and working up the reaction product in the usual manner.

PREPARATION 17.MALEIC ANHYDRIDE ADDUCT or 3-BETA-IIYDROXY-5,7,9 (11) -PREGNATRIEN-20-ONE Similarly, the maletic anhydride adduct of 3- beta hydroxy 5,7,9(11) pregnatrien 20 one, melting point about degrees centigrade, was prepared by refluxing the maleic acid adduct of 3 beta-hydroxy 5,7,9(11) pregnatrien-20-one with Dowtherm for eight hours. The 3-hydroxymaleic anhydride adduct is also obtained by heating the B-hydroxy maleic acid adduct to just above its melting point, which procedure causes Water to be evolved, with the closing of the anhydride ring.

In the same manner as given above, still other 5,7,9(11)-pregnatrien-20-one adducts are prepared from the corresponding 3,22-diacyloxybisn0r-5,7,9(11),20(22) -cholatetraene maleic acid, maleic acid anhydride, and maleic acid diester adducts. Such compounds include the 3-formoxy-5,7,9(l1)-pregnatrien-20-one maleic acid, maleic acid anhydride, dimethyl maleate, diethyl maleate, dibutyl maleate, dioctyl maleate, diisopropyl maleate, dibenzyl maleate and like adducts; the corresponding 3-propionoxy, butyroxy, valeroxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, and similar 20-ketone adducts, including, for example, 3-propionoxy-5,7,9(ll)- pregnatrien-ZO-one dipropyl maleate, 3-benzoyloxy-5,7,9(l1) -pregnatrien-20-one dibenzyl maleate, 3 heptanoyloxy 5,7,9(11) -pregnatrien-20- one dimethyl maleate, 3-valeroyloxy-5,7,9(1l)- pregnatrien-ZO-one maleic acid anhydride adducts, and the like.

Example 1.-Maleic anhydride adduct 0 3-betaacetoxy-21-brom0-5,7,9 (11) -IJregnatrien-20-one To a solution of 2.26 grams of 3-beta-acetoxy- 5,7,9(11)-pregnatrien-20-one maleic anhydride adduct in eighty milliliters of chloroform, cooled to zero degree Centigrade, was added a solution of 840 milligrams of bromine in twenty milliliters of chloroform. The mixture was placed in the refrigerator at zero degree Centigrade. After standing for sixteen hours, the bromine color had disappeared. The solvent was then removed in vacuo at room temperature, and the residue dissolved in twenty milliliters of methylene chloride and diluted with fifty milliliters of isopropyl ether. 3 -beta-acetoxy-21-bromo-5,7,9(11) -pregnatrien- 20-one maleic anhydride adduct, melting at 231-234 degrees centigrade, was obtained. Several recrystallizations from acetone resulted in a purer material melting at 235-2375 degrees Upon cooling, 1.75 grams of crystalline 13 centigrade. The compound has an [alphaJ of plus 118.07 (chloroform).

Analysis:

Calculated C, 61.02; H, 5.88; Br, 15.04 Found 61.74; 5.91; 14.17

In exactly the same manner, the 3-formoxy, 3- propionoxy, 3-butyroxy, 3-valeroyloxy, 3-hexanoyloxy, 3-heptanoyl0Xy, 3-benzoyloxy, and 3-octanoyloxy-Zl-bromo anhydride adducts are obtained from the corresponding 3-acyloxy-5,7,9- (11)-pregnatrien-20-one maleic anhydride adduct.

Example 2.-Dimethyl maleate adduct 0; 3-betaacetozry-21-bromo-5,7,9(11) -pregnatrien20-one Analysis:

Calculated C, 60.31; H, 6.46; Br, 13.84 Found 59.41; 6.25; 15.71

In exactly the same manner, the corresponding diethyl, dipropyl, diisopropyl, dibutyl, diamyl, diheptyl, dioctyl, and like dialkyl maleates of 3 acyloxy 21-bromo-5,7,9(11) -pregnatrien-20- ones, including the 3-formoxy, 3-acetoxy, 3-pr0- pionoxy, S-butyroxy, 3-valeroyloxy, 3-hexanoyloxy, 3-hep-tanoyloxy, 3-benzoyloxy, and 3-octanoyloxy 21 bromo 5,7,9(11) pregnatrien-20- ones, are prepared from the corresponding 3-acy1- oxy-5,7,9(11)-pregnatrien-20-one dialkyl maleates.

Example 3.-Maleic acid adduct of 3-beta-b'enzoyZoxy-Zl -bromo-5,7,9 (11 -pregnatriene-20-one In the same manner as given in the above examples, the maleic acid adduct of 3-beta-benzoyloxy-21-bromo-5,7,9(11) -pregnatrien-20 one is prepared from the maleic acid adduct of 3- beta-benzoyloxy-5,7,9 (11) -pregnatrien-20-one.

Other maleic acid adducts of the present invention include 3-formoxy, 3-acetoxy, 3-propionoxy, 3-butyroxy, 3-valeroyloxy, 3-hexanoyloxy, B-heptanoyloxy, and 3-octanoyloxy-21- bromo-517,901) -pregnatrien-20-one maleic acid adducts, which are prepared from the corresponding 3 acyloxy 5,7,9(11) -pregnatrien-20- one maleic acid adduct as given in the preceding examples.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A 21 bromo 3-acyloxy-5,7,9(11) -pregnatrien-ZO-one adduct of the formula:

CHaBl t=o CH3 ll 1 Qt;

wherein Ac is the residue of an unsubstituted organic monocarboxylic acid containing from one to eight carbon atoms, inclusive, and wherein A is the adduct radical of a dienophile selected from the group consisting of maleic acid, maleic anhydride, and lower-alkyl diesters of maleic acid wherein the esterifying groups contain from one to eight carbon atoms, inclusive. 2. 21 -bromo-3-acetoxy-5,7,9(11)-pregnatrien- 20-one maleic anhydride adduct.

3. 21 -bromo-3-acetoxy-5,'7 ,9 11) -pregnatrien- 20-one dimethyl maleate adduct.

4. A compound of claim 1, wherein A00 is the acetoxy group.

ROBERT I-I. LEVIN. A VERN McIN'IOSI-I, JR. GEORGE B. SPERO.

Name Date Inhofien Oct. 8, 1946 Number 

1. A 21 -BROMO - 3-ACYLOXY-5,7,9(11)-PREGNATRIEN-20-ONE ADDUCT OF THE FORMULA: 